Cellular proliferation is a stringently controlled process, regulated through the activity of extracellular signaling molecules which control the expression of genes that respond to promote or repress growth. Many primary cultured cells demonstrate contact inhibition upon the formation of a confluent monolayer, regardless of the presence of growth factors. This density-dependent negative regulation is believed to be caused by a combination of signaling through soluble polypeptides in the environment of the cell and by cell-cell contact. Upon the attainment of contact inhibition, normal fibroblasts become quiescent and undergo modulation of their redox status to a less reducing state. The confluent state has also been demonstrated to be protective against apoptosis in some cell types. Despite the growing understanding of the cell surface molecules involved in negative growth control, the mechanism for transducing these signals to the nucleus is still not clear. Mitogen-activated protein (MAP) kinases represent a family of signaling proteins which have been implicated in the response of cells to a variety of extracellular stimuli, ranging from growth factors to cellular stresses, though their regulation during contact inhibition has not been well-studied. The overall hypothesis of this proposed work is that the alteration in MKP regulation upon contact inhibition influences the basal activity and stress-stimulated activation of mitogen-activated protein (MAP) kinase pathways. Such changes would be expected to be key in growth regulation, and may also influence the cellular response to stress. The following specific aims will be accomplished: 1) Characterize the causal relationship between MKPs and contact inhibited growth control, 2) Characterize the influence of density-dependent redox state changes on the expression and activity of MKPs, and 3) Characterize the influence of density-dependent changes in MKP signaling on the cellular response to oxidative stress. This research will be accomplished at an undergraduate institution, allowing undergraduates experience in all aspects of the research: performing experiments, analyzing data, and presenting their work. Deregulated MAP kinase activity has been implicated in cancer, atherogenesis, and the immune response; understanding the potential role of MKPs in the density-dependent regulation of MAP kinase pathways may lead to new insights in these disease processes. [unreadable] [unreadable] [unreadable]